The present invention relates to a novel anti-inflammatory ophthalmic solution and the process for preparing the same, and more particularly to an anti-inflammatory ophthalmic solution containing 2-(2-fluoro-4-biphenylyl)propionic acid (hereinafter referred to as "FP") or its ophthalmologically acceptable salt and .beta.-cyclodextrin (hereinafter referred to as ".beta.-CD") or .gamma.-cyclodextrin (hereinafter referred to as ".gamma.-CD") which makes easy operations conducted for diseases in ophthalmic region, and is useful for early recovery or reduction of inflammation by pre- and post-operative topical instillation thereof or by intraocular perfusion with a perfusate to which the instant ophthalmic solution is added, or for treatment of inflammatory eye diseases.
When trauma is inflicted on the local of the eye in human by operation of anterior portion of the eye, such as operation of strabismus, cataract or glaucoma, prostaglandins (hereinafter referred to as "PGs") are biosynthetically produced and liberated from ocular tissue. It is also known that PGs are liberated in large quantities not only by such a mechanical irritation, but also in aqueous humor of the anterior chamber in the eye with a certain kind of uveitis such as Behcet's disease or at the time of glaucomatocyclitic crisis.
On the other hand, it is made clear that the PGs so liberated cause miosis and postoperative inflammation or elevate the intraocular pressure. For this reason, operation of soft cataract, etc. is made after sufficient mydriasis with atropine, etc., but miosis occurs during the operation and it makes the operation difficult. Therefore, there has been attempted oral administration of aspirin or indomethacin which is a nonsteroidal anti-inflammatory agent having an inhibitory effect on biosynthesis of PGs, for the purpose of inhibiting the biosynthesis of PGs which cause such symptoms, making operation easy and reducing complication and inflammation after the operation. However, in case of oral administration of these agents, they must be administered in large amounts for exhibiting their effect, since the amount of migration thereof to the local of the eye is small. On the other hand, administration of aspirin or indomethacin in large amounts accompanies a side effect such as digestive trouble, and is not clinically adoptable.
In order to migrate a drug in as large amount as possible without side effect, direct topical installation to the eye ball or injection to conjunctiva bulbi may be conducted. With respect to the former means, there has been attempted the use of indomethacin in the form of oil preparation, but the stability of the preparation is poor and the feeling in use is bad. Thus the preparation is not useful. With respect to the latter means, it is known that subconjuctival injection of polyphloretin phosphate as an inhibitor of PGs synthesis to a patient in glaucomatocyclitic crisis has an effect of decreasing the intraocular pressure, but it cannot also be habitually, clinically used, because it causes pain to a patient and eye pain or smart feeling is strong.
A nonsteroidal anti-inflammatory agent, FP, developed by S. S. Adams et al has the following structural formula and is a phenylacetic acid derivative as well as ibufenac and ibuprofen and has anti-inflammatory, analgesic and antipyretic effects: ##STR1##
The anti-inflammatory effect of FP administered orally in animals is 14 times the inhibitory effect of indomethacin and 250 times the inhibitory effect of aspirin on carrageenan-induced edema in the pad of hind foot of rat. Also, the inhibitory effect of FP on biosynthesis of PGs from arachidonic acid in lung homogenate of guinea pig is 10 times that of indomethacin and 2,280 times that of aspirin.
Like this, FP has a strong inhibitory effect against quinine or PGs system, and the effect is also proportioned to the strength of the anti-inflammatory action. The effect is the strongest among known nonsteroidal anti-inflammatory agents. Also, strong effects are seen on the inflammatory pain and pyrexia accompanying therewith, and it has been considered that these effects are also largely based on the inhibition of PGs biosynthesis. In addition, FP has also an effect of stabilizing vital membrane, an effect of activating ATPase and an effect of inhibiting the liberation of leucocytes and proteins. Although the combination of the above-mentioned effects probably exerts the anti-inflammatory, analgesic and antipyretic actions, it has been considered that these actions are mainly based on the inhibitory effect on the PGs biosynthesis.
Steven M. Podos et al lately carried out a comparative study of the inhibitory effect of 14 nonsteroidal anti-inflammatory agents on the intraocular pressure elevation and aqueous humor protein increase by biosynthesis of PGs from arachidonic acid in rabbits, and reported that suspenions of indoxole (added with polysorbate), meclofenamic acid, indomethacin and clonixin, including an aqueous solution of FP, exhibited particularly strong inhibitory effects [cf. Invest. Ophthalmol., 15(10), 841 to 844(1976)]. However, it cannot be said that they are preparations completed as an ophthalmic solution or suspension, and they are not clinically usable and are not put to practical use.
It is an object of the present invention to prepare surely a safer opthalmic solution by using FP having a strong inhibitory effect on the PGs biosynthesis, in other words, to provide an ophthalmic solution which is effective even in a lower concentration of FP and can be used in a higher concentration of FP by making FP, which is usually of limited solubility, soluble in a high concentration, and does not show any local irritation and is stable for a long term.
Another object of the invention is to provide a process of preparing the above-mentioned ophthalmic solution.
These and other objects of the present invention will become apparent from the description hereinafter.